Cancer is something that most people are unfortunately very familiar with. I’m going to go out on a limb and say that there is no one who doesn’t have an acquaintance who has been affected by cancer. Cancer is the #2 killer of Americans (behind heart disease), and a lot of us try to adjust our habits and lifestyle to reduce our risk of getting it.

What do you think the greatest risk factor for cancer is? Smoking? Eating red meat? Working with asbestos? It’s actually something that is always affecting us all – age. Cancer has been with humans throughout history, but in the modern age where medicine can keep us alive well past our 80’s we have seen that the risk of cancer always grows steadily as we grow older. This could seem counterintuitive at first – if a person was predisposed to cancer, wouldn’t it manifest sooner? The answer to this question is one of the things that makes cancer unique as a disease, but first you have to know a little bit about:

How Cancer Works

Cancer isn’t caused by some external factor, and it (mostly) isn’t something in your body failing. Cancer is when cells in your own body replicate and divide uncontrollably. Your body relies on its cells to orderly carry about their business, but cancer cells have decided to buck the system and divide as much as they possibly can, regardless of the consequences to the cells around them. Our cells have evolved multiple redundant systems to try to stop cancer from forming, and in order for a cell to become cancerous, each of these systems must be broken one by one.

One of my favorite scientific papers of all time is "The Hallmarks of Cancer" by Hanahan and Weinberg [PDF], a paper so cool that it has its own wikipedia page. If you have a few hours and are inclined to learn everything you could ever hope to know about cancer, you should read it. The authors describe the six main characteristics that all cancers share, and each characteristic represents a failure of one system designed to keep cellular division in check.

So how can these systems break? Let’s say you work in a tiny windowless office like me. Your cruel boss keeps you locked in there, and the only contact you have with the outside is a single lightbulb over the door. When it is time for you to eat lunch, your boss turns the light on from the outside. You see the light on the inside, and eat your lunch. But one day, the circuitry of the light bulb breaks; the lightbulb stays on no matter what the input from the outside is. So, naturally, you just keep eating and eating until you burst.

This is analogous to some factors which control the way cells reproduce. Receptors on the surface of the cell can receive signals from the rest of the body that tell them when to divide. When the receptor receives the signal, it causes a chemical inside the cell to be released that starts the cell division process. If the receptor becomes broken so that it is always “on,” the cell will continue to divide unabated without needing any signals from outside.

This is the first and greatest hallmark of cancer – self-sufficiency in growth signals. The second is like unto it – insensitivity to anti-growth signals. Cellular division is promoted by growth signals and suppressed by anti-growth signals. If the receptor that would normally sense anti-growth signals is broken, it becomes much easier to undergo cellular division.

DNA Damage

It is important to remind ourselves now that each cell in the body has its own copy of our DNA. In order for the effects of these two mutations to be dangerous, they must be present in the same cell. But one can imagine how rare it would be for 1 cell out of our 100 trillion to happen to undergo two extremely rare mutations. So how then does cancer ever arise?

Our cells can be roughly divided into those that actively undergo cell division in order to repopulate our bodies, and those that do not divide much (or at all). The first type, epithelial cells, can be found lining many parts of our body, such as the skin, digestive system, and secretory organs. Another type of rapidly dividing cell can be found inside the bone marrow, where the body's blood is made They repopulate our tissues by undergoing constant (but controlled) division, and their progeny contain the same DNA as the parent cell. This means that a cell whose DNA is damaged passes this mutation on to subsequent generations! An oncogenic mutation that affects an epithelial cell will be present in all future offspring of that cell.

Let’s say you go to the beach when you are 5, and get a bad sunburn. One epithelial cell happens to be damaged in such a way as to allow it to produce its own growth signals. On its own, this is not enough to cause a cancer to form, since other systems can keep this cell in check. But as this cell reproduces, all of its progeny carry this same mutation. When you are 18, you spend too much time in the sun again, and one of these already-mutated cells gets hit by UV light and the gene that creates receptors for anti-growth signals is destroyed. Now you have a cell with two hallmarks of cancer, which will start to grow at an accelerated rate. Over time, this cell population may develop into a malignancy.This is why age is the greatest risk factor for cancer! DNA damage can be cumulative, and oncogenic changes in a stem cell population can be passed down throughout your life. Since it takes several accumulated mutations to cause cancer, the odds of this occurring become greater as you age.

Other Hallmarks

In all, Hanahan and Weinberg enumerate 6 main hallmarks of cancer. The first two (self-sufficiency/insensitivity to growth/anti-growth signals) are straightforward, but the rest are more subtle. There is a process called apoptosis (or cell-suicide) where a cell is induced to kill itself by outside signals. This can be used to control unwanted cells (ex: in utero humans start out with webbed fingers, but apoptosis allows the skin cells to die in between our fingers & subsequently separate into 5 digits). Cancer cells generally have some part of the apoptosis mechanisms/signaling pathways broken, such as inactivation of the p53 tumor suppressor gene.

Tumor cells also need the capability to replicate indefinitely without aging. In each cell division, pieces of the end of the DNA strands are lost. After enough divisions, the genome is broken and the cell dies. Almost all (~85%) cancers have activated the enzyme telomerase, which adds caps back onto the ends of DNA, and this will by-pass normal DNA replication “STOP” signals in cancerous cells, allowing for uncontrolled DNA replication.

For a tumor to grow, it needs a lot of blood. In order to grow beyond a certain size, the tumor must be able to recruit blood vessel construction. This process is called angiogenesis. Tumors can undergo angiogenesis by over expressing factors for blood vessel construction (like vascular endothelial growth factor VEGF) or by suppressing angiogenesis inhibitors (like thrombospondin-1).

Finally, a malignant tumor is able to invade other tissues or travel through the bloodstream. Cells are held in place by a network of proteins called the extracellular matrix (ECM). Tumor cells which express proteins that degrade the ECM can a) escape the ECM of the tumor b) degrade and attack the ECM of other tissues, causing damage. Tumor cells which can invade a blood vessel are then free to travel through the body, and are called metastatic.

You would think that since all cancers had so much in common, they would be easy to treat. The truth is that it not nearly that simple. Each cell type has different machinery, and can become cancerous through the activation of different pathways. The cell has many different ways to acquire each of the six hallmarks, leading to hundreds of different cancer types, each one different from the other. This is what makes cancer so hard to treat. But the better we get at characterizing a person’s cancer on the molecular level, the more we can develop effective tools to fight very specific factors that make the cells cancerous.

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